Project Summary Alzheimer?s Disease (AD) has devastating consequences on an individual?s wellbeing, community and society. The root cause of AD has not been clearly elucidated. The amyloid protein A?42 has been associated with AD pathology in form amyloid plaques that are thought to cause neuronal death in Alzheimer?s patients. Intensive research has identified the ?-, ? and ?- secretases as processing enzymes that process the amyloid precursor protein (APP) to produce soluble forms of APP, A? proteins and intracellular signaling domains. However, how APP processing is controlled and modulated by other proteins, and how different forms of the APP proteolytic product function, remains unclear. In this supplemental application, we propose to identify the interaction partners of APP, a mutant and pathogenic form of APP, and their cleavage products, to elucidate pathways involved in the trafficking and processing of APP, and the function of various proteolytic products under normal and pathological conditions. We will utilize APEX2 fusion proteins, a novel approach to allow extremely accurate labeling of closely associated protein to achieve this goal. We will conduct this set of experiments in the mouse olfactory system. In Alzheimer?s disease, olfactory dysfunction is one of the earliest manifestations of pathology. Expression of mutant forms of APP causes dramatic alteration of axon projection patterns and synaptic connections. The physical separation of the olfactory sensory neurons and their axons in different compartments make it an easily accessible system to dissociate protein functions in the axons from those in the cell body. This study will provide much needed in vivo examination of pathways that process and interact with APP. This study is relevant to the parent grant. The main goal of the parent grant is to understand the cellular and molecular mechanisms of the development plasticity that permit precise neuronal connections in the brain. During early postnatal brain development, a high level of plasticity allows the neurons to make precise and functional connections. This plasticity declines in the adults, impairing the ability of the nervous system to repair damages and restore function. The specific goals of the parent study are to identify the cellular and molecular mechanisms underlying axon targeting in early development and to identify the mechanism that controls the critical period in the mouse olfactory system. This supplement will extend the study to the function of APP and A?42 to understand pathological conditions that interfere with developmental plasticity.